Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy

Abstract Background The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent P...

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Autores principales:	Xin Peng, Shaolu Zhang, Wenhui Jiao, Zhenxing Zhong, Yuqi Yang, Francois X. Claret, Moshe Elkabets, Feng Wang, Ran Wang, Yuxu Zhong, Zhe-Sheng Chen, Dexin Kong
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Hydroxychloroquine BKM120 Autophagy Homologous recombination repair ROS PI3K Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/46925260bbed4e66aa320b5ae39a76b7
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spelling	oai:doaj.org-article:46925260bbed4e66aa320b5ae39a76b72021-12-05T12:10:13ZHydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy10.1186/s13046-021-02176-21756-9966https://doaj.org/article/46925260bbed4e66aa320b5ae39a76b72021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02176-2https://doaj.org/toc/1756-9966Abstract Background The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer. Methods The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining. Results HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51. Conclusions Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the “off target” effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer.Xin PengShaolu ZhangWenhui JiaoZhenxing ZhongYuqi YangFrancois X. ClaretMoshe ElkabetsFeng WangRan WangYuxu ZhongZhe-Sheng ChenDexin KongBMCarticleHydroxychloroquineBKM120AutophagyHomologous recombination repairROSPI3KNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-21 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Hydroxychloroquine BKM120 Autophagy Homologous recombination repair ROS PI3K Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Hydroxychloroquine BKM120 Autophagy Homologous recombination repair ROS PI3K Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Xin Peng Shaolu Zhang Wenhui Jiao Zhenxing Zhong Yuqi Yang Francois X. Claret Moshe Elkabets Feng Wang Ran Wang Yuxu Zhong Zhe-Sheng Chen Dexin Kong Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy
description	Abstract Background The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer. Methods The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining. Results HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51. Conclusions Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the “off target” effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer.
format	article
author	Xin Peng Shaolu Zhang Wenhui Jiao Zhenxing Zhong Yuqi Yang Francois X. Claret Moshe Elkabets Feng Wang Ran Wang Yuxu Zhong Zhe-Sheng Chen Dexin Kong
author_facet	Xin Peng Shaolu Zhang Wenhui Jiao Zhenxing Zhong Yuqi Yang Francois X. Claret Moshe Elkabets Feng Wang Ran Wang Yuxu Zhong Zhe-Sheng Chen Dexin Kong
author_sort	Xin Peng
title	Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy
title_short	Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy
title_full	Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy
title_fullStr	Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy
title_full_unstemmed	Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy
title_sort	hydroxychloroquine synergizes with the pi3k inhibitor bkm120 to exhibit antitumor efficacy independent of autophagy
publisher	BMC
publishDate	2021
url	https://doaj.org/article/46925260bbed4e66aa320b5ae39a76b7
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Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy

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